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Investigating Potential Cardiovascular Toxicity of Two Anti-Leukemia Drugs of Asciminib and Ponatinib in Zebrafish Embryos.

ABSTRACT: BCR-ABL, a fusion protein kinase, is a druggable target exclusively expressed in patients with chronic myeloid leukemia (CML). Several anti-leukemia medicines targeting this protein have been developed in recent years. However, therapeutic options are limited for CML patients bearing multiple BCR-ABL1 mutations. Ponatinib (PON), a potent tyrosinase inhibitor, was one of the approved drugs for managing BCR-ABL1 T315I mutant disease. However, treatment of patients with PON reported severe side effects related to cardiovascular events. Asciminib (ASC) was the first allosteric inhibitor approved to target the myristoyl pocket of BCR-ABL protein to inhibit protein activity. The different mechanism of inhibition opens the possibility of co-exposure with both medicines. Reports on cardiovascular side effects due to the combination use of PON + ASC in pre-clinical and clinical studies are minimal. Thus, this study aimed to observe the potential cardiovascular-related side effect after co-exposure to ASC and PON using zebrafish as an animal model. In this study, zebrafish were acutely exposed to both compounds. The cardiovascular physiology parameters and gene expression related to cardiovascular development were evaluated. We demonstrate that combining ASC with PON at no observed effect concentration (NOEC) did not cause any significant change in the cardiac performance parameter in zebrafish. However, a significant increase in nkx2.5 expression level and a substantial decrease in blood flow velocity were recorded, suggesting that combining these compounds at NOEC can cause mild cardiovascular-related side effects.

SUBMITTER: Lin HC

PROVIDER: S-EPMC9570146 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Investigating Potential Cardiovascular Toxicity of Two Anti-Leukemia Drugs of Asciminib and Ponatinib in Zebrafish Embryos.

Lin Huan-Chau HC Saputra Ferry F Audira Gilbert G Lai Yu-Heng YH Roldan Marri Jmelou M MJM Alos Honeymae C HC Aventurado Charlaine A CA Vasquez Ross D RD Tsai Guan-Jhe GJ Lim Ken-Hong KH Hsiao Chung-Der CD

International journal of molecular sciences 20221003 19

BCR-ABL, a fusion protein kinase, is a druggable target exclusively expressed in patients with chronic myeloid leukemia (CML). Several anti-leukemia medicines targeting this protein have been developed in recent years. However, therapeutic options are limited for CML patients bearing multiple BCR-ABL1 mutations. Ponatinib (PON), a potent tyrosinase inhibitor, was one of the approved drugs for managing BCR-ABL1 T315I mutant disease. However, treatment of patients with PON reported severe side eff ...[more]

PMID: 36233014

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Project description:BackgroundPonatinib and asciminib are approved for third-line therapy in chronic-phase chronic myeloid leukemia (CP-CML) and are the only drugs approved for patients with the T315I mutation in the United States. In Europe, only ponatinib is approved for patients with the T315I mutation.MethodsClinical trials evaluating ponatinib or asciminib in patients with relapsed and refractory (R/R) CP-CML who failed one or more second-generation TKIs or had the T315I mutation were identified in a systematic review of medical literature databases. A matching-adjusted indirect comparison (MAIC) analysis with individual patient-level data with ponatinib was used to balance baseline characteristics between ponatinib and asciminib groups. After matching, the response rate was calculated using the MAIC weight for each patient and the difference in response rate was calculated using a two-independent proportion Z-test. Cumulative rates of BCR::ABL1 IS ≤1% and major molecular response (MMR) in patients without baseline response were compared. Patients were further stratified by T315I mutation status.ResultsThe MAIC included four trials (ponatinib: NCT02467270, NCT01207440; asciminib: NCT02081378, NCT03106779). In patients without baseline response of BCR::ABL1 IS ≤1%, the adjusted BCR::ABL1 IS ≤1% rate difference with ponatinib vs. asciminib was 9.33% (95% confidence interval [CI]: 0.79%-17.86%; adjusted MMR rate difference: 6.84% [95% CI: -0.95%-14.62%]) by 12 months in favor of ponatinib. In patients with the T315I mutation, adjusted BCR::ABL1 IS ≤1% rate difference with ponatinib vs. asciminib was 43.54% (95% CI: 22.20%-64.87%; adjusted MMR rate difference: 47.37% [95% CI: 28.72%-66.02%]) by 12 months.ConclusionAfter key baseline characteristics adjustment, cumulative BCR::ABL1 IS ≤1% and MMR rates were statistically higher with ponatinib than asciminib in patients without a baseline response in most of the comparisons by 12 months. Favorable efficacy outcomes observed in ponatinib vs. asciminib were consistently stronger in the T315I mutation subgroup.

Dataset Information

Investigating Potential Cardiovascular Toxicity of Two Anti-Leukemia Drugs of Asciminib and Ponatinib in Zebrafish Embryos.

Publications

Investigating Potential Cardiovascular Toxicity of Two Anti-Leukemia Drugs of Asciminib and Ponatinib in Zebrafish Embryos.

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